Ligustrazine is the principle bioactive alkaloid in the widely-used Chinese herb Chuan Xiong rhizome. Herein, a series of novel derivatives has been designed as human carbonic anhydrases inhibitors (hCAIs) starting from the natural product Ligustrazine inserted as a tail instead of the 4-fluorophenyl tail of SLC-0111, a front-runner selective hCA IX inhibitor currently in clinical trials as antitumor/antimetastatic agent. Other derivatives were designed via incorporation of different linkers, of amide and ester type, or incorporation of different zinc anchoring groups such as secondary sulfamoyl and carboxylic acid functionalities. The newly designed molecules were prepared following different synthetic pathways, and were assessed for their inhibitory actions against four isoforms: the widespread cytosolic (hCA I and II), and the transmembrane tumor-related (hCA IX and XII). The primary sulfonamides efficiently inhibited the target hCA IX and hCA XII in the nanomolar range (K_Is: 6.2–951.5 nM and 3.3–869.3 nM, respectively). The most selective hCA IX inhibitors 6c and 18 were assessed for their potential anticancer effects, and displayed anti-proliferative activity against MCF-7 cancer cell line with IC₅₀s of 11.9 and 36.7 μM, respectively. Molecular modelling studies unveiled the relationship between structural features and inhibitory profiles against the off-target hCA II and the target, tumor-related isoforms hCA IX and XII.

川芎嗪是广泛使用的中药川芎根中的主要生物活性生物碱。在此，一系列新的衍生物被设计为人类碳酸酐酶抑制剂 ( h CAIs)，从作为尾部插入的天然产物川芎嗪开始，而不是 SLC-0111 的 4-氟苯基尾部，SLC-0111 是一种领先的选择性h CA IX 抑制剂目前在临床试验中作为抗肿瘤/抗转移剂。其他衍生物是通过设计的掺入不同的酰胺和酯类型的接头，或掺入不同的锌锚定基团，例如仲氨磺酰基和羧酸官能团。新设计的分子是按照不同的合成途径制备的，并评估了它们对四种同种型的抑制作用：广泛的细胞溶质（h CA I 和 II）和跨膜肿瘤相关的（h CA IX 和 XII）。伯磺胺类药物在纳摩尔范围内有效抑制靶标h CA IX 和h CA XII（ K _I s：分别为 6.2–951.5 nM 和 3.3–869.3 nM）。最具选择性的h CA IX 抑制剂6c和18评估了它们的潜在抗癌作用，并显示出对 MCF-7 癌细胞系的抗增殖活性，IC ₅₀ s 分别为 11.9 和 36.7 μM。分子模型研究揭示了结构特征和对脱靶 hCA II 和靶标、肿瘤相关异构体h CA IX 和 XII 的抑制谱之间的关系。